Vascular endothelial growth factor (VEGF, also referred to as VEGFA in contrast to other members of the VEGF family) is pivotal in many physiological and pathological processes. It is primarily known for its key role in the stimulation of angiogenesis, with a potent mitogenic effect on vascular endothelial cells from arteries, veins and lymphatics. VEGF also promotes vasodilatation by inducing the production of nitric oxide and prostacyclin by endothelial cells. In addition, VEGF is involved in hematopoietic development and chemotaxis of monocytes, regulation of osteoclast differentiation, stimulation of surfactant production, and has neurotrophic and neuroprotective effects on neuronal and glial cells. Elevated circulating VEGF levels have been observed in vascular disease (ischemic heart disease, heart failure, stroke), and in various other disorders, including diabetes, cognitive decline and dementia, reproductive, immune-inflammatory disorders, and neoplastic diseases. Administration of VEGF promotes angiogenesis in patients with critical leg ischemia, as well as in animal models of coronary and limb ischemia. VEGF inhibitors such as bevacizumab and sorafenib have been successfully used to inhibit angiogenesis in several tumors, in macular degeneration and in rheumatoid arthritis.
However, despite the considerable toxicity associated with VEGF inhibitor drugs, to date there have been no pharmacogenomic studies to identify potential sub-groups of responders partly because the genetic determinants of VEGF concentrations remain poorly understood.
Indeed, although the heritability of circulating VEGF levels is very high, ranging between 60 and 80%, few studies have assessed the relationship between circulating VEGF levels and genetic variants.
Candidate gene studies exploring associations between VEGF polymorphisms and circulating VEGF levels have yielded controversial results. Eight studies have found significant associations with candidate polymorphisms (rs699947, rs1570360, rs833061, rs2010963, rs3025039 and −2549 18 bp I/D) in the promoter, 5′ and 3′ untranslated region of the VEGF gene. However, several other studies did not identify any association with these and other VEGF SNPs.
While several studies have examined the association of candidate genetic variants with VEGF gene expression in pathological tissues, little is known about the genetic variants influencing VEGF expression in normal cells.
Therefore, there is a need for greater understanding of polymorphisms linked to VEGF levels, in order to identify patients who are more likely to respond favorably to anti-VEGF and pro-angiogenic VEGF based treatments. Such therapies can have major side-effects, and optimizing the risk to benefit ratio of their administration could lead to substantial improvements in patient care.